ArticleDrug metabolism and disposition: the biological fate of chemicals2010
Ecto-5'-nucleotidase and thiopurine cellular circulation: association with cytotoxicity.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 18 citations in OpenAlex.
- Thiopurine pharmacogenomics: association of SNPs with clinical response and functional validation of candidate genes.Pharmacogenomics · 2014Trial
- An NT5E loss-of-function variant permits tissue inflammation and hypertension in systemic lupus erythematosus.iScience · 2026Article
- Revisiting the Role of Thiopurines in Inflammatory Bowel Disease Through Pharmacogenomics and Use of Novel Methods for Therapeutic Drug Monitoring.Frontiers in pharmacology · 2018Review
- Population pharmacokinetics of fludarabine in patients with aplastic anemia and Fanconi anemia undergoing allogeneic hematopoietic stem cell transplantation.Bone marrow transplantation · 2017Article
- Genome-Wide Study of Response to Platinum, Taxane, and Combination Therapy in Ovarian Cancer: In vitro Phenotypes, Inherited Variation, and Disease Recurrence.Frontiers in genetics · 2016Article
- Gene expression and thiopurine metabolite profiling in inflammatory bowel disease - novel clues to drug targets and disease mechanisms?PloS one · 2013Article
- Gene set analysis of purine and pyrimidine antimetabolites cancer therapies.Pharmacogenetics and genomics · 2011Article
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Thiopurine drugs such as 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used to treat acute lymphoblastic leukemia of childhood. To test the hypothesis that variation in the expression of genes within the "thiopurine pathway" might influence 6-MP and 6-TG sensitivity, we generated basal gene expression profiles and IC(50) values for both of these thiopurine drugs using a model system consisting of 194 Human Variation Panel lymphoblastoid cell lines. Association analysis showed that thiopurine S-methyltransferase, ecto-5'-nucleotidase (NT5E), and multidrug resistance protein 4 (ABCC4) expression were correlated with thiopurine cytotoxicity. Those observations suggested the possible existence of a "thiopurine cellular circulation" involving nucleotide efflux by ABCC4, hydrolysis of thiopurine nucleotide monophosphates outside of the cell by NT5E, and subsequent transport of thiopurine nucleosides back into the cell by nucleoside transporters. The existence of this cellular circulation was confirmed by a series of functional experiments performed with cultured cells stably or transiently transfected with ABCC4 and/or NT5E. Because of the central role of NT5E in this cellular circulation, the NT5E gene was resequenced using 287 DNA samples from three ethnic groups, with the identification of 68 single nucleotide polymorphisms (SNPs), 46 of which were novel. Several SNPs in the 5'-flanking region of NT5E were highly correlated with expression, rs9450278 having the lowest p value (p = 2.4 × 10(-10), R = -0.376). The thiopurine cellular circulation and genetic polymorphisms for genes encoding the proteins involved should be incorporated into future studies of thiopurine drug therapy and effect.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.